Cape gooseberry (Physalis peruviana L.) as a functional food for metabolic health: A narrative review of glucose and lipid regulatory effects

3.2.1. Benefits of CP consumption in the management of metabolic syndrome-related diseases: diabetes and obesity

Metabolic syndrome is a chronic and progressive pathophysiological condition that increases the risk of diseases such as dyslipidemia, type 2 diabetes mellitus, and obesity [1,2]. The pathophysiology of diabetes and obesity is complex and multifactorial, involving chronic inflammation, oxidative stress, insulin resistance, and deregulated lipid metabolism. Dysfunctional adipose tissue releases pro-inflammatory mediators that promote the infiltration of various immune cells, mainly macrophages, generating a pro-inflammatory environment with the participation of cytokines such as Tumor Necrosis Factor Alpha (TNF-α) and Interleukin 6 (IL-6). These cytokines play a key role in impairing insulin signaling, which in the long term leads to systemic insulin resistance and the exacerbation of metabolic dysfunction [18–21]. Oxidative stress, defined by an imbalance between pro-oxidants and antioxidant defenses, is another critical factor contributing to the development of insulin resistance, β-cell dysfunction, and lipid peroxidation. These processes culminate in progressive metabolic deterioration and increase the risk of cardiovascular disease and type 2 diabetes [22,23].

Given their high morbidity and mortality rates, type 2 diabetes mellitus and obesity represent a major public health challenge [1,2]. Based on data from the International Diabetes Federation Diabetes Atlas, it is estimated that around 537 million adults between the ages of 20 and 79 are living with diabetes globally, a number expected to rise to 643 million by 2030 [24]. Conversely, the World Health Organization reported that in 2022, approximately 2.5 billion adults were overweight, with around 890 million (16%) classified as obese [25]. A key strategy to prevent and control these pathologies is the adoption of a nutritionally balanced diet rich in vegetables and fruits. These foods contain secondary metabolites with well-documented biological activities [3,4].

CP, a fruit that has gained increasing attention in recent decades, is an example of a nutrient-rich food with potential health benefits [5]. Historically, this fruit has been used to treat digestive disorders such as indigestion and gastric acidity, as well as to strengthen the immune system. In Indonesia, it is commonly used for the treatment of diabetes mellitus and related conditions [6], while in China, it is employed for its anticancer, detoxifying, and anti-inflammatory properties [7]. In Latin America, CP has traditionally been used to treat conditions such as asthma, dermatitis, fever, ulcers, and inflammation, as well as to help reduce blood cholesterol levels [8–10].

The ethnopharmacological use of CP has generated great scientific interest, resulting in numerous in vitro and in vivo studies. These investigations have provided evidence supporting the therapeutic properties of compounds present in the fruit, which may play a crucial role in regulating glucose metabolism and lipid profiles, both of which are key factors in metabolic syndrome.

3.2.1.1. Preclinical studies

To evaluate the metabolic effects of functional foods, several biomarkers have been employed, including fasting blood glucose, HbA1c, triglycerides, high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol, insulin, as well as markers of inflammation and oxidative stress. Animal studies consistently show that CP consumption exerts beneficial effects in models of obesity and dyslipidemia by improving lipid profiles, lowering blood glucose, and mitigating inflammation and oxidative damage. A summary of the main findings is provided in Table 1.

Table 1. Primary outcomes of preclinical trials on the effects of CP consumption in diabetes management and lipid profile modulation.

STZ: streptozotocin; SOD: superoxide dismutase; CAT: catalase; GPT: glutamic pyruvic transaminase; LDL: low-density lipoprotein; HDL: high-density lipoprotein; mRNA: messenger ribonucleic acid; TNF-α: tumor necrosis factor alpha; IL: interleukin, TLR4: toll-like receptor 4; FasN: fatty acid synthase; INSR: insulin receptor; LPL: lipoprotein lipase; INSR: insulin receptor; PPARγ: peroxisome proliferator-activated receptor gamma; BMI: body mass index; MDA: malondialdehyde; AGE: advanced glycation end-products.

The effects of filtered and freeze-dried CP juice were evaluated in Wistar rats with diabetes induced by streptozotocin (STZ), followed by 24 hours of ad libitum access to a 20% sucrose solution to exacerbate hyperglycemia, as described by Mora et al. [12]. The juice was administered orally at a dose of 250 mg/kg/day for 15 days. The treatment led to a reduction in blood glucose levels exceeding 30%, along with increased ferric reducing ability of plasma and enhanced activity of key antioxidant enzymes, including superoxide dismutase (SOD) and catalase (CAT). Additionally, a decrease in lipid peroxidation and protein oxidation was observed. These findings support the hypoglycemic and antioxidant potential of CP in diabetic models.

In a separate study, Dewi et al. [26] investigated the effects of filtered CP juice (excluding seeds and skins) and quercetin on insulin resistance and oxidative stress in 36 Wistar rats. The animals were fed a high-fat diet and received STZ to induce insulin resistance. Over a 28-day period, the rats were treated via oral gavage with doses of 5 and 25 ml/kg/day, as well as quercetin at 2.2 and 30 mg/kg/day. The administration of the higher doses (25 ml/kg/day of CP juice and 30 mg/kg/day of quercetin) resulted in a significant increase in total antioxidant capacity and adiponectin levels. This enhancement in adiponectin was suggested to be mediated through the upregulation of peroxisome proliferator-activated receptor-γ (PPAR-γ) mRNA, potentially induced by the flavonoid content of the treatments [26].

In a comparable approach, the protective role of CP on oxidative damage was assessed in a type 1 diabetes model using 27 Wistar rats, as detailed by Fazilet et al. [13]. The intervention involved the intraperitoneal administration of a CP extract (1 ml/kg, twice weekly) combined with 2 g of CP powder dissolved in drinking water, provided ad libitum over a 60-day period. This combined treatment resulted in a significant increase in glutathione levels and a reduction in blood glucose and malondialdehyde (MDA), a biomarker of lipid peroxidation. These findings support the potential of CP as a therapeutic agent for managing hyperglycemia and oxidative stress in diabetes.

A study conducted in an acute hyperlipidemia model using 24 Mus musculus var. Swiss mice demonstrated the hypolipidemic effects of CP, as reported by Campos et al. [27]. Hyperlipidemia was induced by Triton, and the intervention consisted of a single oral dose of dehydrated CP juice, prepared from filtered fresh fruit, administered at 0.05 g/100 g and 0.2 g/100 g of body weight. After 24 hours, a significant reduction in plasma cholesterol and triglyceride levels was observed. These effects were attributed to the flavonoid content of CP, suggesting its potential utility as a rapid-acting agent in the management of hyperlipidemia.

Furthermore, two studies conducted by Ramadan et al. [28] explored the hypolipidemic and antioxidant properties of different CP preparations in male albino rats with a high-fat diet. In the first study, Ramadan et al. [28] supplemented the diet with filtered and pasteurized juice at concentrations of 5% and 15% for 60 days. This intervention led to significant reductions in total cholesterol, triglycerides, and LDL levels, as well as an increase in HDL levels. Histological analyses also revealed normalization of liver tissues, suggesting that the observed effects may be attributed to the flavonoid content of the juice and its capacity to inhibit LDL oxidation [28]. In a subsequent study, Ramadan [29] administered freeze-dried CP pomace (containing skins and seeds) at dietary concentrations of 10% and 30% for 60 days. Similar improvements in lipid profiles were observed, along with protection against hepatic oxidative stress and the development of fatty liver in rats fed a high-fat diet [29].

In addition, the metabolic effects of whole CP pulp (including peel and seeds) were evaluated in male C57BL/6 mice with diet-induced obesity in a study conducted by Pino-de la Fuente et al. [14]. In this study, 32 obese mice were fed a high-fat diet and treated for 56 days with a dietary supplementation of 300 mg/kg/day of CP pulp. The intervention effectively prevented visceral fat accumulation, reduced fasting blood glucose levels, and decreased lipid peroxidation in both liver and muscle tissues. Furthermore, the treatment led to a marked reduction in the expression of pro-inflammatory markers, including TNF-α mRNA, IL-6, IL-1β, and TLR4. These findings suggest that the daily consumption of whole CP pulp may serve as a promising nutritional strategy to prevent insulin resistance and liver damage in the context of diet-induced obesity.

In a complementary study, Ángel-Martín et al. [30] supplemented the diet of 64 obese Wistar rats with 8% (w/w) of finely chopped fresh CP for 16 days. The intervention not only prevented excessive weight gain but also significantly improved lipid profiles and reduced visceral and subcutaneous fat accumulation. Notably, beneficial effects were also observed in vital organs such as the liver and pancreas, likely due to the high content of polyphenols and vitamins A and C. Furthermore, modulation of key metabolic genes, including INSR, PPARγ, FasN, and LPL, was reported, reinforcing the fruit’s potential role in improving metabolic health [30].

Furthermore, the effects of a methanolic extract of CP on hepatic oxidative stress and metabolic syndrome were examined in obese female Wistar rats by Moussa et al. [15]. The extract was administered orally at doses of 200 and 400 mg/kg/day for 56 days. The intervention led to significant improvements in multiple metabolic parameters, including reductions in body mass index (BMI), total cholesterol, triglycerides, glucose levels, and the insulin resistance index. In addition, HDL cholesterol levels increased, accompanied by favorable modulation of adipokines, as evidenced by decreased leptin and elevated adiponectin levels. The treatment also attenuated oxidative stress and systemic inflammation, as indicated by lower levels of TNF-α, IL-2, IL-6, and C-reactive protein. Collectively, these findings highlight the potential of CP methanolic extract as a therapeutic agent for alleviating key features of metabolic syndrome, such as hyperlipidemia, diabetes mellitus, and fatty liver disease.

Additionally, Aljadani et al. [31] investigated the effects of freshly prepared CP juice, obtained from filtered pulp of ripe fruits, on rats with STZ-induced type 1 diabetes. The juice was administered orally at a dose of 5 ml/kg/day for 56 days, either alone or in combination with metformin. The intervention led to a significant reduction in blood glucose levels, improved lipid profiles, and renal protection, as evidenced by decreased levels of kidney damage markers. Oxidative stress was also markedly attenuated, with lower MDA concentrations and enhanced activity of antioxidant enzymes such as CAT and glutathione reductase. Furthermore, the juice inhibited the formation of advanced glycation end-products (AGEs), which are closely associated with diabetic complications. Notably, co-administration with metformin amplified these protective effects, underscoring the potential of CP juice as an effective adjunct therapy for glycemic control and renal protection in diabetes [31].

Most recently, Tshibangu et al. [32] evaluated the antihyperglycemic potential of a methanolic dried extract derived from CP fruit powder Naval Medical Research Institute (NMRI) white mice with glucose-induced hyperglycemia. Hyperglycemia was triggered by the oral administration of a glucose solution (4 g/kg body weight/day), and the extract was administered daily at doses of 200 and 400 mg/kg over a 213-day treatment period. Control groups received distilled water, glibenclamide (5 mg/kg), or metformin (25 mg/kg). Blood glucose levels were assessed at 30 and 150 minutes after glucose loading. Both extract doses significantly reduced glycemia at both time points, with the 400 mg/kg dose exhibiting effects comparable to those of glibenclamide and metformin. These findings further support the antidiabetic potential of CP and are consistent with previous studies highlighting its therapeutic properties [32].

3.2.1.1.1. Analysis of preclinical studies focused on diabetes.

Preclinical studies consistently demonstrate that CP exerts beneficial metabolic effects, including reductions in fasting glucose, triglycerides, total cholesterol, and LDL cholesterol, along with increases in HDL levels and antioxidant enzyme activity (Table 1). However, despite this general consistency, the interpretation of the findings is challenged by notable methodological heterogeneity.

To assess the impact of CP on blood glucose regulation, most studies employed STZ to induce diabetes in Wistar rats. An exception was the study by Tshibangu et al. [32], who induced hyperglycemia in NMRI white mice via oral glucose administration.

Instead of oral supplementation, the study by Fazilet et al. [13] administered an intraperitoneal extract supplemented with 2 g of CP fruit powder in water to male Wistar rats with STZ-induced type 1 diabetes for 60 days. This intervention resulted in decreased blood glucose and (MDA, a marker of lipid peroxidation), alongside elevated glutathione levels. A similar treatment duration was used by Aljadani et al. [31], who administered CP juice orally (5 ml/kg/day) for 56 days in a comparable diabetic model. While both studies reported improvements in glycemic control and oxidative stress, Aljadani et al. [31] observed broader benefits, including enhanced lipid profiles, reduced levels of serum advanced AGEs, and increased activity of antioxidant enzymes such as CAT and glutathione reductase.

Although the study by Pino-de la Fuente et al. [14] employed a treatment duration comparable to that of Fazilet et al. [13] and Aljadani et al. [31], their study diverged in key methodological aspects. Unlike the others, Pino-de la Fuente et al. [14] did not induce diabetes via STZ; instead, insulin resistance was triggered through a high-fat diet in obese male C57BL/6 mice. Additionally, different matrices were used for fruit delivery: fruit powder dissolved in water [13], juice [31], and pulp incorporated into the diet [14]. These discrepancies limit direct comparisons. Nevertheless, all three studies consistently reported reductions in blood glucose and lipid peroxidation, two key biomarkers across the investigations, suggesting that both Wistar rats and C57BL/6 mice are suitable models and that various CP preparations (juice, powder, and pulp) retain biologically active compounds with hypoglycemic and antioxidant properties.

The experimental design proposed by Dewi et al. [26] closely resembles that of Aljadani et al. [31], as both employed STZ to induce diabetes and administered CP juice at comparable doses (5 and 25 ml/kg/day). However, Dewi et al. [26] applied the treatment for only 28 days, half the duration used by Aljadani et al. [31]. Moreover, the studies assessed different sets of biomarkers, preventing a comprehensive comparison. Dewi et al. [26] primarily reported increased total antioxidant capacity, without evaluating other parameters such as AGEs or antioxidant enzyme activity. Therefore, conclusions regarding treatment duration and effect consistency remain limited.

A methodology similar to that of Dewi et al. [26] was proposed by Mora et al. [12], as the same STZ-induced diabetic model and short intervention periods (15 and 28 days, respectively) were used in both studies. While the preparation methods were largely analogous, Mora et al. [12] administered a dehydrated juice form, which resulted in dosage units being expressed in milligrams rather than milliliters. Due to differences in the selected biomarkers, the results could not be directly compared. Nonetheless, both studies demonstrated that CP exerted significant antioxidant activity.

3.2.1.1.2. Analysis of preclinical studies focused on obesity.

As shown in Table 1, to explore the effects of CP on obesity and dyslipidemia, most experimental models employed high-fat diets to induce metabolic alterations. An exception was the study by Campos et al. [27], who induced hyperlipidemia acutely using Triton in Swiss mice. These studies also varied in the rodent species used, which adds to the methodological diversity observed across the literature. Nevertheless, a common trend emerged: CP consistently demonstrated the ability to reduce total cholesterol and triglyceride levels, and in several cases, to improve the lipoprotein profile (LDL/HDL).

Whole CP fruit was administered to obese rodents in both studies conducted by Pino-de la Fuente et al. [14] and Ángel-Martín et al. [30], using C57BL/6 mice and Wistar rats, respectively. However, differences in the form of administration and treatment duration (56 days in the former and 16 days in the latter) preclude direct comparison of dosages. Despite these differences, both studies reported reductions in blood glucose levels, indicating that the hypoglycemic effects of CP can emerge within a short timeframe (16 days) and be sustained with longer interventions (56 days). Comparison of other biomarkers was not possible, as the two studies targeted different physiological pathways: Pino-de la Fuente et al. [14] focused on inflammation and oxidative stress, whereas Ángel-Martín et al. [30] investigated lipid metabolism through enzyme activity and gene expression. Importantly, both studies yielded favorable results for their respective endpoints.

Supporting these findings, Moussa et al. [15] conducted a study with a similar treatment duration (56 days), in which a methanolic extract of CP was administered to obese Wistar rats. This study stands out for its use of 70% methanol during sample preparation, an approach that effectively extracted bioactive constituents responsible for the observed biological effects. Their results, particularly regarding reductions in pro-inflammatory cytokines TNF-α and IL-6, closely aligned with those reported by Pino-de la Fuente et al. [14], reinforcing the anti-inflammatory potential of the fruit in obesity-related contexts.

Additional evidence comes from studies where the whole fruit was not administered. For instance, Ramadan et al. [28] administered filtered juice devoid of seeds and skin, while Ramadan [29] used only the skin and seeds. Despite these differences in sample composition, both studies reported significant improvements in lipid profiles, including reductions in total cholesterol, triacylglycerols, and LDL, alongside increases in HDL. These findings suggest that the bioactive compounds responsible for these effects are distributed across different parts of the fruit. Moreover, both studies employed a treatment duration of 60 days, similar to the 56-day protocol used by Pino-de la Fuente et al. [14]. However, due to differences in biomarker selection, cross-study comparisons remain limited.

In contrast to these long-term studies, Campos et al. [27] implemented a single-dose, acute model of hyperlipidemia. They administered dehydrated CP juice at two doses (0.05 g/100 g and 0.2 g/100 g body weight) and observed significant reductions in cholesterol and triglyceride levels within 24 hours. These results demonstrate that the beneficial effects of CP on lipid metabolism may be observed rapidly, following even a single administration, a particularly promising finding.

3.2.1.2. Clinical studies

Despite the existing gaps in preclinical research, the promising results reported in individual studies targeting diabetes and obesity have led to the initiation of clinical trials investigating the therapeutic potential of CP in the management of metabolic diseases, particularly diabetes. To date, clinical evidence on the effects of CP in humans remains limited and preliminary, with only two available studies reporting heterogeneous outcomes regarding insulin sensitivity and blood glucose levels. A summary of the main findings from these studies is provided in Table 2.

Table 2. Primary results of clinical trials on the effects of CP consumption on diabetes management.

EGFR: Epidermal growth factor receptor

The effects of CP on insulin signaling and its potential antidiabetic properties were evaluated in a group of 18 healthy male volunteers aged 20–50 years by Vaillant et al. [16]. During the first phase of the study, blood samples were collected after fasting and again 6 hours after participants consumed 250 g of fresh CP along with a standardized breakfast and lunch. Subsequently, the participants consumed 150 g of CP daily for 19 days, after which new blood samples were analyzed. The results showed that CP intake was associated with the modulation of biological pathways related to insulin signaling, including the epidermal growth factor receptor (EGFR) and the PI3K/Akt/mTOR cascade. A total of 74 plasma metabolites were identified, with 11 metabolites common to both phases of the study. These findings suggest that CP exerts a measurable influence on insulin-related pathways, although this effect appears to diminish after cessation of consumption, yet remains detectable 24 hours post-intake.

In contrast, Ludeña-Meléndez et al. [17] conducted a quasi-experimental study involving 28 young adults (aged 18–26) with overweight or obesity, who were randomly assigned to either a control group or an intervention group. The intervention group consumed 50 g of CP daily for 21 days, while both groups followed a standardized low-carbohydrate diet. Although a significant reduction in fasting blood glucose was observed in both groups, no statistically significant difference was found between them. These results suggest that in non-diabetic individuals under dietary control, CP does not exert an additional hypoglycemic effect. This contrasts with previous findings in diabetic populations, where CP consumption has been associated with significant improvements in glycemic control [17].

3.2.1.2.1. Analysis of clinical studies.

A comparison of the two clinical studies that met the inclusion criteria reveals that, while both were based on preclinical evidence indicating that CP consumption can improve insulin sensitivity and reduce blood glucose levels, they pursued different objectives. The study by Vaillant et al. [16] investigated the acute and medium-term effects of CP intake on plasma metabolites related to insulin signaling pathways. The findings demonstrated a positive modulation of the PI3K/Akt/mTOR signaling cascade. Although the study did not evaluate clinical parameters such as blood glucose or insulin sensitivity, its findings suggest that compounds present in CP may exert subtle metabolic effects in healthy individuals.

In contrast, the study conducted by Ludeña-Meléndez et al. [17] aimed to evaluate the impact of CP consumption on fasting blood glucose in young adults with overweight or obesity. While a reduction in blood glucose was observed in both the intervention and control groups, no statistically significant difference was detected between them, and therefore, no glycemic benefit could be attributed to CP intake. This lack of effect may be explained by several methodological factors. First, both groups followed a standardized low-carbohydrate diet, which likely contributed to reduced glucose levels in both cases, diminishing the ability to isolate the specific effects of the fruit. Second, the participants did not present with marked metabolic impairment (e.g., type 2 diabetes), limiting the potential to observe clinically relevant improvements in glycemic control. Additionally, the mode of administration, the moderate daily dose, and the short intervention period may have further reduced the bioavailability and efficacy of the active compounds. The limited sample size also constrained the statistical power of the study.

3.2.1.3. Limitations of preclinical and clinical studies

The analysis of both preclinical and clinical studies revealed several limitations inherent to each type of study. In the case of preclinical evaluation of effects of CP on glucose metabolism, substantial variability in study design, including differences in disease induction methods, animal models, delivery matrices (pulp, extract, juice, and powder), doses, durations (ranging from 1 to 213 days), and biomarkers assessed, was observed. Despite this methodological diversity, the collective evidence supports the hypoglycemic and antioxidant effects of CP, often in line with conventional treatments. Nonetheless, greater standardization in experimental protocols is essential to improve the comparability and interpretability of future findings.

Similarly, in the context of preclinical studies focused on obesity, it is important to highlight a key insight from the collective analysis: despite notable differences in experimental models, animal species, administration forms, and biomarker panels, CP consistently showed beneficial effects on plasma lipid levels, glycemia, oxidative stress, and inflammation. This consistency supports the hypothesis that the bioactive compounds of the fruit retain their efficacy across various biological contexts. Nevertheless, further research is warranted to evaluate CP across short-, medium-, and long-term treatment durations, and using standardized formulations (e.g., whole pulp, freeze-dried pomace, and filtered pasteurized juice). Future studies should harmonize the selection of biomarkers for lipid metabolism, oxidative stress, and inflammation to facilitate cross-study comparisons and clarify the mechanisms underlying the therapeutic potential of CP.

Turning to clinical evidence, it is important to highlight that both studies included small sample sizes and short intervention periods. For instance, in the study by Ludeña-Meléndez et al. [17], the daily dose of CP administered was substantially lower than the recommended thresholds, considering both the glycemic index of the fruit and the World Health Organization’s guidelines on daily fruit consumption [33]. These limitations weakened the statistical robustness and clinical significance of the findings. As a result, current clinical evidence remains inconclusive, and firm conclusions regarding the effects of CP on insulin sensitivity and glycemic regulation cannot yet be drawn.

Accordingly, these deficiencies underscore the need for well-designed randomized controlled trials with increased sample size and clearly defined CP doses and formulations. Consideration should also be given to including populations with clearly defined metabolic disorders in addition to healthy individuals. Future studies should explore the short- and long-term effects of CP consumption on oxidative stress, inflammation, glycemic control, and lipid metabolism. Notably, a recent study by Ndahura et al. [76] proposed a protocol for a randomized controlled trial aimed at evaluating the effect of CP consumption on blood glucose control in patients with type 2 diabetes.

The above strategies would contribute to providing a more accurate assessment of the potential of fruit as an adjuvant in the prevention and/or treatment of metabolic disorders such as diabetes and obesity.

3.2.2. Bioactive compounds of cape gooseberry fruit and their role in diabetes and obesity management

In individuals with obesity, dysfunctional adipose tissue persistently secretes pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, which activate immune cells, particularly macrophages, thereby initiating a state of chronic inflammation accompanied by oxidative stress [18,19]. Elevated TNF-α levels have been directly linked to the onset of insulin resistance, contributing to the development and progression of type 2 diabetes mellitus and further amplifying the systemic inflammatory response [20–22].

Phytochemical analyses of CP have revealed the presence of key secondary metabolites, including carotenoids, flavonoids, phytosterols, terpenes, and withanolides, which exhibit antioxidant, anti-inflammatory, antidiabetic, and anti-obesity activities. These bioactive compounds are considered the principal mediators of the potential health benefits associated with CP consumption, particularly in the prevention and/or management of type 2 diabetes mellitus and obesity (Fig. 1).

Figure 1. Bioactive secondary metabolites identified in CP including carotenoids, flavonoids, phytosterols, terpenes, and withanolides, and their associated antioxidant, anti-inflammatory, antidiabetic, and anti-obesity properties. [Click here to view]

The collective findings from preclinical and clinical investigations suggest potential molecular mechanisms by which the secondary metabolites of CP exert their biological activities (Table 3).

Table 3. Biological effects of bioactive secondary metabolites present in CP as complementary therapies for diabetes and lipid profile disorders.

IL: interleukin; IFN-γ: interferon-gamma; NF-?B: nuclear factor-κB; TNF-α: tumor necrosis factor alpha; NLRP3: nod-like receptor protein 3; COX-2: cyclooxygenase-2; PGE2: prostaglandin E 2; NO: nitric oxide; LDL: low-density lipoprotein; HDL: high-density lipoprotein; VLDL: very-low-density lipoprotein; IDL: intermediate-density lipoprotein; MPO: myeloperoxidase; ROS: reactive oxygen species; iNOS: inducible nitric oxide synthase; SOD: superoxide dismutase; CAT: catalase; GR: glutathione reductase; GPx: glutathione peroxidase; GLUT: glucose transporter; LOX: lipoxygenase; PKB: protein kinase B; IRS: insulin receptor substrate; BAT: brown adipose tissue; MCP-1: monocyte chemoattractant protein-1; MAPK: mitogen-activated protein kinase; GSR: glutathione-disulfide reductase; GSTA4: glutathione S-transferase 4; HO-1: heme oxygenase-1; GCK: glucokinase; AMP: activated protein kinase; ACC: acetyl-CoA carboxylase; HbA1c: glycated hemoglobin.

As shown in Table 3, the carotenoids, flavonoids, phytosterols, terpenes, and withanolides present in CP exhibit significant antioxidant and anti-inflammatory activity through multiple mechanisms. These bioactive compounds act as potent antioxidants by stimulating key enzymes, including SOD, CAT, glutathione reductase (GR), and glutathione peroxidase (GPx), while simultaneously reducing lipid peroxidation and the generation of nitric oxide (NO) and reactive oxygen species (ROS). Additionally, they have been observed to increase the levels of the T-Nrf2 protein and heme oxygenase-1 (HO-1) mRNA.

The anti-inflammatory response is mediated through the inhibition of various pro-inflammatory mediators, such as NO, prostaglandin E2 (PGE2), and multiple cytokines. Furthermore, these compounds suppress the activity of enzymes including cyclooxygenase-2 (COX-2), lipoxygenase (LOX), inducible nitric oxide synthase (iNOS), and myeloperoxidase (MPO), while activating glutathione reductase (GR), glutathione S-transferase A4 (GSTA4), and HO-1. Consequently, the expression of key inflammatory markers such as NLRP3, TLR4, MCP-1, PPARα, and PPARγ is downregulated, while crucial signaling pathways, including JAK2/STAT3, JNK/p38 MAPK, and TLR4/MyD88/NF-κB P65, are modulated. These antioxidant and anti-inflammatory mechanisms may help explain the regulatory effects of these metabolites on glucose levels and lipid profiles. Several studies have established a direct correlation between oxidative stress, chronic inflammation, and the onset or progression of metabolic disorders such as obesity and diabetes [19,23].

Research has further demonstrated that flavonoids, phenolic acids, phytosterols, and terpenes exert antidiabetic effects by lowering blood glucose and HbA1c levels, enhancing insulin secretion, and promoting glycogen synthesis in the liver. These compounds activate the PI3K/p-Akt signaling pathway, facilitate glucose uptake by stimulating the translocation of glucose transporters (GLUT)-4, GLUT-2, and GLUT-1 transporters, and inhibit key enzymes involved in carbohydrate metabolism, such as α-glucosidase, α-amylase, and maltase. Additionally, they regulate the phosphorylation of IκBα/NF-κB and normalize the expression of key metabolic proteins, including protein kinase B (PKB), insulin receptor substrates (IRS-1 and IRS-2), and (GLUT-2 and GLUT-4). These bioactive compounds also enhance the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in adipose tissue, liver, and muscles, while increasing glucokinase (GCK) levels and boosting the activity of enzymes such as glucose-6-phosphate dehydrogenase and phosphohexose isomerase. Moreover, they help balance gluconeogenic enzymes, including glucose-6-phosphatase, fructose-1,6-bisphosphatase, and lactate dehydrogenase, contributing to improved glycemic control (Table 3 for further details).

Carotenoids and certain flavonoids, including quercetin, rutin, and myricetin, have also attracted attention for their notable antihyperlipidemic and anti-obesity effects. These bioactive compounds reduce cholesterol, LDL, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), triglyceride, and triacylglycerol levels, while downregulating PPARγ expression. Simultaneously, they enhance HDL levels and promote increased energy expenditure. Notably, these compounds contribute to weight loss and activate brown adipose tissue, thereby amplifying their impact on lipid metabolism (Table 3 for further details).

3.2.3. Development and processing of functional foods based on cape gooseberry: a supporting role

To promote the inclusion of CP in the diet of individuals with diabetes and dyslipidemia, it is not enough to provide scientific evidence supporting its health benefits in both patients and healthy populations. It is also essential to improve the shelf life of the fruit and develop multiple formulations that retain its bioactive and medicinal properties.

CP is a highly perishable fruit with a short post-harvest shelf life, requiring rapid commercialization [34]. Due to this limitation, various preservation and processing methods have been evaluated [35].

The implementation of these strategies should not only aim to extend shelf life but also to broaden the market reach, facilitating access to a wider consumer base and enabling international commercialization. Among the methods developed to preserve CP are blanching and osmotic dehydration [36], hot air drying [37], high hydrostatic pressure [38], combined with heat dehydration and freeze-drying [39,40]. These methods offer specific advantages and limitations depending on their ability to preserve the functional, nutritional, and sensory properties of the fruit.

Techniques such as hot air drying, high hydrostatic pressure, freeze-drying, and convection–infrared drying have been identified as viable alternatives for maintaining the bioactive compounds in CP, particularly phenolics, which are closely associated with the antioxidant and anti-inflammatory activity of the fruit [36–40]. Thus, CP preserved using these techniques may continue to provide health benefits to individuals with diabetes and obesity. Nevertheless, further preclinical and clinical trials are required to assess the effects of preserved CP on biomarkers related to oxidative stress, inflammation, diabetes, and dyslipidemia.

It is important to emphasize that in methods such as hot air drying and freeze-drying, standardizing processing temperature and time is critical to optimizing outcomes and minimizing alterations in nutritional quality, sensory attributes, and bioactive compound content [37,39,40].

Finally, although osmotic dehydration effectively preserves certain nutritional components, its use is contraindicated in people with diabetes and obesity due to the addition of an 80° Brix sucrose syrup, making it unsuitable for these populations [36]. In contrast, processing strategies that increase the concentration of beneficial compounds, such as spray drying optimized to preserve carotenoids and flavonoids, could contribute to the formulation of functional foods with targeted metabolic effects.

Despite the limitations of some of the preservation methods, several researchers have proposed that these techniques could serve as a foundation for the development of functional foods derived from CP. In recent years, a number of these methods have been explored and applied in the formulation of various CP-based products, as shown in Table 4. However, many of these formulations contain added sugars, such as sucrose, glucose, and maltodextrin, which contradict their intended purpose, as they may be harmful to individuals with diabetes and metabolic disorders.

Table 4. Functional food prototypes based on CP.

RDI: Reference Daily Intake; w/w: Weight per weight.

Conversely, formulations designed specifically for patients with diabetes and lipid profile disorders have focused on nutritional enhancement through the enrichment of vitamins and minerals. While such products may contribute to overall health, they often fail to go beyond meeting basic nutritional needs. One notable exception is the formulation incorporating Lactobacillus plantarum, which has demonstrated probiotic properties [41].

Prospective evaluations of the long-term effects will be crucial to determine the actual functional potential of CP-based formulations. Specifically, it will be necessary to assess their impact on key biomarkers associated with oxidative stress, inflammation, diabetes, and dyslipidemia. These studies will provide essential evidence to support the rational development of functional foods targeted at individuals with metabolic disorders.